RECOMBINATE

Antihemophilic Factor (Recombinant)

Lyophilized Powder for Reconstitution for injection

Reconstitute with 5 mL of Sterile Water for Injection using double-ended

needles

DESCRIPTION

RECOMBINATE [Antihemophilic Factor (Recombinant)] is a glycoprotein

synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line.

In culture, the CHO cell line secretes recombinant Factor VIII (rFVIII) into the

cell culture medium. The rFVIII is purified from the culture medium utilizing a

series of chromatography columns. A key step in the purification process is an

immunoaffinity chromatography methodology in which a purification matrix,

prepared by immobilization of a monoclonal antibody directed to Factor VIII, is

utilized to selectively isolate the rFVIII in the medium. The synthesized rFVIII

produced by the CHO cells has the same biological effects as human Factor VIII.

Structurally the protein has a similar combination of heterogenous heavy and light

chains as found in human Factor VIII.

RECOMBINATE is formulated as a sterile, nonpyrogenic, off-white to faint

yellow, lyophilized powder preparation of concentrated recombinant Factor VIII

for intravenous injection. RECOMBINATE is available in single-dose vials,

which contain nominally 250, 500, 1000, 1500, and 2000 International Units per

vial. When reconstituted with the appropriate volume of diluent, the product

contains the following stabilizers in maximum amounts: For 5 mL reconstitution

volume: 25 mg/mL Albumin (Human), 0.40 mg/mL calcium, 3 mg/mL

polyethylene glycol (3350), 360 mEq/L sodium, 110 mM histidine, 1.5 µg/Factor

VIII International Unit (IU) polysorbate-80. Recombinant Von Willebrand Factor

(rVWF) is coexpressed with the rFVIII and helps to stabilize it. The final product

contains not more than 2 ng rVWF/IU rFVIII, which will not have any clinically

relevant effect in patients with von Willebrand’s disease. The product contains no

preservative.

Manufacturing of RECOMBINATE is shared by Baxter Healthcare Corporation

and Wyeth BioPharma. The recombinant Antihemophilic Factor Concentrate (For

Further Manufacturing Use), is produced by Baxter Healthcare Corporation and

Wyeth BioPharma (For Further Manufacturing Use) and subsequently formulated

and packaged at Baxter Healthcare Corporation.

Each vial of RECOMBINATE is labeled with the Factor VIII activity expressed

in IU per vial. Biological potency is determined by an in vitro assay which is

referenced to the World Health Organization (WHO) International Standard for

Factor VIII:C Concentrate.

CLINICAL PHARMACOLOGY

Factor VIII is the specific clotting factor deficient in patients with hemophilia A

(classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized

by hemorrhages, which may occur spontaneously or after minor trauma. The

administration of RECOMBINATE provides an increase in plasma levels of

Factor VIII and can temporarily correct the coagulation defect in these patients.

Pharmacokinetic studies on sixty-nine (69) patients revealed the circulating mean

half-life for RECOMBINATE to be 14.6 ± 4.9 hours (n=67), which was not

statistically significantly different from plasma-derived HEMOFIL M,

[Antihemophilic Factor (Human), Method M, Monoclonal Purified]. The mean

half-life of HEMOFIL M was 14.7 ± 5.1 hours (n=61). The actual baseline

recovery observed with RECOMBINATE was 123.9 ± 47.7 IU/dL (n=23), which

is significantly higher than the actual HEMOFIL M baseline recovery of 101.7 ±

31.6 IU/dL (n=61). However, the calculated ratio of actual to expected recovery

with RECOMBINATE (121.2 ± 48.9%) is not different on average from

HEMOFIL M (123.4 ± 16.4%).

The clinical study of RECOMBINATE in previously treated patients (individuals

with hemophilia A who had been treated with plasma derived Factor VIII) was

based on observations made on a study group of 69 patients. These individuals

received cumulative amounts of Factor VIII ranging from 20,914 to 1,383,063 IU

over the 48 month study. Patients were given a total of 17,700 infusions totaling

28,090,769 IU RECOMBINATE.

These patients were successfully treated for bleeding episodes on a demand basis

and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding

episodes successfully managed include hemarthroses, soft tissue and muscle

bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24

procedures on 13 patients were performed during this study. These included

minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy

and liver transplant) procedures. Hemostasis was maintained perioperatively and

postoperatively with individualized Factor VIII replacement.

A study of RECOMBINATE in previously untreated patients was also performed

as part of an ongoing study. The study group was comprised of seventy-nine (79)1

patients, of whom seventy-six (76) had received at least one infusion of

RECOMBINATE. To date, this cohort has been given 12,209 infusions totaling

over 11,277,043 IU of RECOMBINATE. Hemostasis was appropriately managed

in spontaneous bleeding episodes, intracranial hemorrhage and surgical

procedures.

INDICATIONS and USAGE

The use of RECOMBINATE [Antihemophilic Factor (Recombinant)] is indicated

in hemophilia A (classical hemophilia) for the prevention and control of

hemorrhagic episodes.2 RECOMBINATE is also indicated in the perioperative

management of patients with hemophilia A (classical hemophilia).

RECOMBINATE can be of therapeutic value in patients with acquired Factor

VIII inhibitors not exceeding 10 Bethesda Units per mL.3 In clinical studies with

RECOMBINATE, patients with inhibitors who were entered into the previously

treated patient trial and those previously untreated children who have developed

inhibitor activity on study, showed clinical hemostatic response when the titer of

inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the

dosage of RECOMBINATE should be controlled by frequent laboratory

determinations of circulating Factor VIII levels as well as the clinical status of the

patient.

RECOMBINATE is not indicated in von Willebrand’s disease.

CONTRAINDICATIONS

RECOMBINATE is contraindicated in patients who have manifested life-

threatening immediate hypersensitivity reactions, including anaphylaxis, to the

product or its components, including bovine, mouse or hamster proteins.

WARNINGS

General

The clinical response to RECOMBINATE may vary. If bleeding is not controlled

with the recommended dose, the plasma level of factor VIII should be determined

and a sufficient dose of RECOMBINATE should be administered to achieve a

satisfactory clinical response. If the patient’s plasma factor VIII level fails to

increase as expected or if bleeding is not controlled after the expected dose, the

presence of an inhibitor (neutralizing antibodies) should be suspected and

appropriate testing performed. (see PRECAUTIONS - Monitoring Laboratory

Tests).

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with RECOMBINATE and have been manifested as dizziness pruritus, rash, urticaria, flushing, angioedema/face swelling, laryngeal edema, dyspnea, pallor, pyrexia, nausea, paresthesia, hypotension, and loss of consciousness. Discontinue RECOMBINATE if symptoms occur and seek immediate emergency treatment. RECOMBINATE contains trace amounts of bovine proteins, mouse immunoglobulin G (MuIgG), and hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies

Patients treated with antihemophilic factor (AHF) products should be carefully

monitored for the development of factor VIII inhibitors by appropriate clinical

observations and laboratory tests. Inhibitors have been reported following

administration of RECOMBINATE predominantly in previously untreated and

minimally treated patients. The risk of developing inhibitors is highest during the

first 20 exposure days. If expected plasma factor VIII activity levels are not

attained, or if bleeding is not controlled with an expected dose, an assay that

measures factor VIII inhibitor concentration should be performed (see

PRECAUTIONS - Monitoring Laboratory Tests).

.

PRECAUTIONS

General

Certain components used in the packaging of this product contain natural rubber

latex.

Identification of the clotting defect as a Factor VIII deficiency is essential

before the administration of RECOMBINATE [Antihemophilic Factor

(Recombinant)] is initiated. No benefit may be expected from this product in

treating other deficiencies.

Formation of Antibodies to Mouse, Hamster or Bovine Protein

As RECOMBINATE contains trace amounts of mouse protein (maximum of 0.1

ng/IU RECOMBINATE), hamster protein (maximum of 1.5 ng CHO protein/IU

RECOMBINATE), and bovine protein (maximum of 1 ng BSA/IU

RECOMBINATE) the remote possibility exists that patients treated with this

product may develop hypersensitivity to these non-human mammalian proteins.

Information for Patients

The patient and physician should discuss the risks and benefits of this product.

Allergic type hypersensitivity reactions have been observed with

RECOMBINATE. Patients should be informed of the early signs of

hypersensitivity reactions including hives, generalized urticaria, tightness of the

chest, wheezing, hypotension, symptoms of laryngeal edema, and anaphylaxis.

Patients should be advised to discontinue use of the product and contact their

physician if these symptoms occur. Additionally, patients should be informed

that local tissue irritation may occur when infusing RECOMBINATE

reconstituted with 5 mL sWFI.

Monitoring Laboratory Tests

Monitor plasma factor VIII activity levels by the one-stage clotting assay

to confirm the adequate factor VIII levels have been achieved and

maintained, when clinically indicated. (see DOSAGE AND

ADMINISTRATION).

Monitor for development of factor VIII inhibitors. Perform assay to

determine if factor VIII inhibitor is present if expected factor VIII activity

plasma levels are not attained, or if bleeding is not controlled with the

expected dose of RECOMBINATE. Use Bethesda Units (BU) to titer

inhibitors.

o If the inhibitor is less than 10 BU per mL, the administration of

additional RECOMBINATE concentrate may neutralize the

inhibitor, and may permit an appropriate hemostatic response.

o Adequate hemostasis may not be achieved if Inhibitor titers are

above 10 BU per mL. The inhibitor titer may rise following

RECOMBINATE infusion as a result of an anamnestic response to

factor VIII. The treatment or prevention of bleeding in such

patients requires the use of alternative therapeutic approaches and

agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

RECOMBINATE was tested for mutagenicity at doses considerably exceeding

plasma concentrations of Factor VIII in vitro and at doses up to ten times the

expected maximum clinical dose in vivo, and did not cause reverse mutations,

chromosomal aberrations, or an increase in micronuclei in bone marrow

polychromatic erythrocytes. Long-term studies in animals have not been

performed to evaluate carcinogenic potential.

Pediatric Use

RECOMBINATE is appropriate for use in children of all ages, including the

newborn. Safety and efficacy studies have been performed in both previously

treated (n=23) and previously untreated (n=75) children. (See Clinical

Pharmacology and Precautions).

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted

with RECOMBINATE. The safety of RECOMBINATE for use in pregnant

women has not been established. It is not known whether RECOMBINATE can

cause fetal harm when administered to a pregnant woman or can affect

reproductive capacity. Physicians should carefully consider the potential risks

and benefits for each specific patient before prescribing RECOMBINATE.

RECOMBINATE should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many

drugs are excreted into human milk, caution should be exercised if

RECOMBINATE is administered to nursing mothers. RECOMBINATE should

be given to nursing mothers only if clinically needed.

ADVERSE REACTIONS

Adverse Reactions from Clinical Trials

During controlled clinical studies with RECOMBINATE enrolling 210 subjects,

the most commonly reported adverse drug reactions were chills, flushing, rash

and epistaxis.

System Organ Class

(SOC)

Preferred

MedDRA Term

Number of

Subjects

Percent of

Evaluable

Subjects*

GASTROINTESTINAL

DISORDERS

Nausea 1 0.48

GENERAL

DISORDERS AND

ADMINISTRATION

SITE CONDITIONS

Chills

Fatigue

Pyrexia

3

1

1

1.43

0.48

0.48

INFECTIONS AND

INFESTATIONS

Ear infections 1 0.48

INVESTIGATIONS Acoustic

stimulation tests

abnormal

1 0.48

MUSCULOSKELETAL

AND CONNECTIVE

TISSUES DISORDERS

Pain in extremity 1 0.48

NERVOUS SYSTEM

DISORDERS

Dizziness

Tremors

1

1

0.48

0.48

RESPIRATORY,

THORACIC AND

MEDIASTINAL

DISORDERS

Pharyngolaryngeal

pain

1 0.48

SKIN AND

SUBCUTANEOUS

TISSUE DISORDERS

Hyperhidrosis

Pruritus

Rash

Rash

maculopapular

1

1

2

1

0.48

0.48

0.95

0.48

VASCULAR

DISORDERS

Epistaxis

Flushing

Hematoma

Hypotension

Pallor

Peripheral

coldness

1†

2

1

1

1

1

0.48

0.95

0.48

0.48

0.48

0.48

* Number of evaluable subjects experiencing the event/total number of evaluable subjects [% relative to 210, the total number of unique subjects who received at least 1 infusion of RECOMBINATE]. †One subject experienced 11 events of epistaxis.

During the Previously Treated Patients (PTP) study, none of the 71 subjects developed de novo evidence of Factor VIII inhibitor. However, during the phase II/III portion of the study, 1 subject with a history of inhibitors exhibited inhibitor activity at 6 months (0.8 Bethesda Units [BU]), which resolved by 9 months. One other subject in this study had detectable Factor VIII inhibitor at baseline (1.26 BU) and exhibited an anamnestic response at 6 months (10.3 BU). During a prospective pharmaco-surveillance study of subjects who received batches of RECOMBINATE containing modestly increased Chinese Hamster Ovary (CHO) cell protein levels, none of the 34 treated subjects developed a Factor VIII inhibitor.

During the Previously Untreated Patients (PUP) study, 22 of the 73 evaluable subjects developed inhibitors to Factor VIII. Of these, 13 subjects displayed no detectable Factor VIII inhibitors at study exit.

Post-Marketing Adverse Reactions

In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience. These adverse reactions are listed by MedDRA (version 12.1) System Organ Class (SOC), then by MedDRA coding system Preferred Term in order of severity. BLOOD AND LYMPHATIC SYSTEM DISORDERS: Factor VIII inhibition CARDIAC DISORDERS: Tachycardia, Cyanosis GASTROINTESTINAL DISORDERS: Vomiting, Abdominal pain GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malaise, Injection site reactions, Chest pain, Chest discomfort IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity NERVOUS SYSTEM DISORDERS: Loss of consciousness, Headache, Paresthesia RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea, Cough, Laryngeal edema SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Urticaria, Erythema DOSAGE and ADMINISTRATION

Each vial of RECOMBINATE is labeled with the Factor VIII activity expressed

in IU per vial. This potency assignment is referenced to the World Health

Organization International Standard for Factor VIII:C Concentrate and is

evaluated by appropriate methodology to ensure accuracy of the results.

The expected in vivo peak increase in Factor VIII level expressed as IU/dL of

plasma or % (percent) of normal can be estimated by multiplying the dose

administered per kg body weight (IU/kg) by two. This calculation is based on the

clinical findings of Abildgaard et al4 and is supported by the data generated by

419 clinical pharmacokinetic studies with RECOMBINATE in 67 patients over

time. This pharmacokinetic data demonstrated a peak recovery point above the

pre-infusion baseline of approximately 2.0 IU/dL per IU/kg body weight.

Examples (Assuming patient’s baseline Factor VIII level is at <1%):

(1) A dose of 1750 IU RECOMBINATE administered to a 70 kg patient, i.e. 25

IU/kg (1750 IU/70 kg), should be expected to cause a peak post-infusion

Factor VIII increase of 25 IU/kg x 2 (IU/dL)/(IU/kg) = 50 IU/dL (50% of

normal).

(2) A peak level of 70% is required in a 40 kg child. In this situation the dose

would be 70 IU/dL/[2(IU/dL)/(IU/kg)] x 40 kg = 1400 IU.

Recommended Dosage Schedule

Physician supervision of the dosage is required. The following dosage schedule

may be used as a guide.

Hemorrhage

Degree of hemorrhage

Required peak post-infusion Factor

VIII activity in the blood (as % of

normal or IU/dL plasma)

Frequency of Infusion

Early hemarthrosis or muscle

bleed or oral bleed 20-40

Begin infusion every 12 to 24 hours

for one-three days until the bleeding

episode is resolved (as indicated by

pain), or healing is achieved.

More extensive hemarthrosis,

muscle bleed, or hematoma 30-60

Repeat infusion every 12 to 24

hours for (usually) three days or

more until pain and disability are

resolved.

Life threatening bleeds such as

head injury, throat bleed, severe

abdominal pain

60-100

Repeat infusion every 8 to 24 hours

until threat is resolved.

Surgery

Type of operation

Minor surgery, including tooth

extraction 60-80

A single infusion plus oral

antifibrinolytic therapy within one

hour is sufficient in approximately

70% of cases.

Major surgery 80-100

(pre- and post-operative)

Repeat infusion every 8 to 24 hours

depending on state of healing

If bleeding is not controlled with the recommended dose, the plasma level of

Factor VIII should be determined and a sufficient dose of RECOMBINATE

should be administered to achieve a satisfactory clinical response

The careful control of the substitution therapy is especially important in cases of

major surgery or life threatening hemorrhages. In presence of a low titer

inhibitor, doses larger than those recommended may be necessary as per standard

care.

Although dosage can be estimated by the calculations above, it is strongly

recommended that whenever possible, appropriate laboratory tests including

serial Factor VIII assays be performed on the patient’s plasma at suitable intervals

to assure that adequate Factor VIII levels have been reached and are maintained.

Patients should be evaluated for the development of Factor VIII inhibitors, if the

expected plasma Factor VIII activity levels are not attained, or if bleeding is not

controlled with an appropriate dose.

Reconstitution: Use Aseptic Technique

1. Bring RECOMBINATE, (dry factor concentrate) and Sterile Water for

Injection, USP, (diluent) to room temperature.

2. Remove caps from concentrate and diluent vials.

3. Cleanse stoppers with germicidal solution and allow to dry prior to use. Place

vials on a flat surface

4. Remove protective covering from one end of double-ended needle and insert

exposed needle through the center of the stopper.

5. Remove protective covering from other end of double-ended needle. Invert

diluent vial over the upright RECOMBINATE vial, then rapidly insert free

end of the needle through the RECOMBINATE vial stopper at its center. The

vacuum in the vial will draw in the diluent.

6. Disconnect the two vials by removing needle from diluent vial stopper, then

remove needle from RECOMBINATE vial. Swirl gently until

RECOMBINATE is completely dissolved, otherwise active material will be

removed by the filter needle. After reconstitution, the solution should be

colorless to faint yellow, and substantially free from foreign particles.

NOTE: Do not refrigerate after reconstitution. (See Administration)

Administration: Use Aseptic Technique

RECOMBINATE is administered by intravenous (IV) injection after

reconstitution.

Administer at room temperature.

RECOMBINATE should be administered not more than 3 hours after

reconstitution.

Intravenous Syringe Injection

Parenteral drug products should be inspected for particulate matter and

discoloration prior to administration, whenever solution and container permit. The

solution should be colorless to faint yellow in appearance. If not, do not use the

solution and notify Baxter immediately.

Plastic syringes are recommended for use with this product since proteins such as

RECOMBINATE tend to stick to the surface of glass syringes.

1. Attach filter needle to a disposable syringe and draw back plunger to admit air

into the syringe.

2. Insert the needle into reconstituted RECOMBINATE.

3. Inject air into vial and then withdraw the reconstituted material into the syringe.

4. Remove and discard the filter needle from the syringe; attach a suitable needle

and inject intravenously as instructed under Rate of Administration.

5. If a patient is to receive more than one vial of RECOMBINATE, the contents

of multiple vials may be drawn into the same syringe by drawing up each vial

through a separate unused filter needle. Filter needles are intended to filter the

contents of a single vial of RECOMBINATE only.

Rate of Administration

The rate of administration should be a rate that ensures the comfort of the patient.

Preparations of RECOMBINATE can be administered at a rate of up to 5 mL per

minute when reconstituted with 5 mL of sWFI.

The pulse rate should be determined before and during administration of

RECOMBINATE. Should a significant increase in pulse rate occur, reducing the

rate of administration or temporarily halting the injection usually allows the

symptoms to disappear promptly.

HOW SUPPLIED

RECOMBINATE is available in five different strengths in single-dose vials. The

strength is designated on the outer box and on the vial label using the following

color codes:

Color Code Dosage Strength RECOMBINATE Supplied with

5 mL sWFI

Light blue bar 220 – 400 IU per vial NDC 0944-2841-15

Pink bar 401-800 IU per vial NDC 0944-2842-15

Green bar 801-1240 IU per vial NDC 0944-2843-15

Purple bar 1241-1800 IU per vial NDC 0944-2844-15

Orange bar 1801-2400 IU per vial NDC 0944-2845-15

RECOMBINATE is packaged with 5 mL of Sterile Water for Injection, USP, a

double-ended needle, a filter needle, one physician insert and one patient insert.

Storage

RECOMBINATE can be refrigerated [2° - 8°C (36° - 46°F)] or stored at room

temperature, not to exceed 30°C (86°F). Avoid freezing to prevent damage to the

diluent vial. Do not use beyond the expiration date printed on the box.

CLINICAL STUDIES

Over the investigational period of the original safety and efficacy study of

RECOMBINATE, none of the 69 subjects without an inhibitor at entry into the

study, developed an inhibitor. In the previously untreated patient group there

were 73 eligible subjects with Factor VIII levels less than or equal to 2% who

received at least one RECOMBINATE treatment (median days 100, range 3-821)

and who were tested for an inhibitor after treatment with RECOMBINATE. Of

this group, 23 individuals (32%) developed a detectable inhibitor (median days on

treatment at time of detection 10, range 3-69) and of these, 8 subjects (11%)

showed a titer greater than 10 B.U.

REFERENCES

1. Bray GL, Gomperts ED, Courter S, Gruppo R, et al: A Multicenter Study of

Recombinant Factor VIII (Recombinate): Safety, Efficacy, and Inhibitor Risk

in Previously Untreated Patients with Hemophilia A Blood 83:2428-2435,

1994

2. White GC, McMillan CW, Kingdon HS, et al: Use of recombinant

antihemophilic factor in the treatment of two patients with classic hemophilia.

New Eng J Med 320:166-170, 1989

3. Kessler CM: An Introduction to Factor VIII Inhibitors: The Detection and

Quantitation. Am J Med 91 (Suppl 5A):1S-5S, 1991

4. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with

glycine-precipitated Factor VIII. New Eng J Med 275:471-475, 1966

To enroll in the confidential, industry-wide Patient Notification System, call

1-888-UPDATE U (1-888-873-2838).

Baxter, RECOMBINATE, and HEMOFIL, are trademarks of Baxter International

Inc.

Manufactured by:

Baxter Healthcare Corporation

Westlake Village, CA 91362 USA

U.S. License No. 140

Printed in USA

Issued: March 2010

Patient Information

RECOMBINATE

[Antihemophilic Factor (Recombinant)]

This leaflet summarizes important information about RECOMBINATE. Please

read it carefully before using this medicine. This information does not take the

place of talking with your healthcare provider, and it does not include all of the

important information about RECOMBINATE. If you have any questions after

reading this, ask your healthcare provider.

Do not attempt to self-infuse unless you have been taught how by your doctor

or hemophilia center.

What is RECOMBINATE [Antihemophilic Factor (Recombinant)]?

RECOMBINATE is a medicine used to replace clotting factor (Factor VIII or

antihemophilic factor) that is missing in people with hemophilia A (also called

“classic” hemophilia). Hemophilia A is an inherited bleeding disorder that

prevents blood from clotting normally.

RECOMBINATE is used to prevent and control bleeding in people with

hemophilia A.

RECOMBINATE is not used to treat von Willebrand’s Disease.

Who should not use RECOMBINATE [Antihemophilic Factor

(Recombinant)]?

You should not use RECOMBINATE if you

are allergic to mouse, hamster or bovine proteins.

are allergic to any ingredients in RECOMBINATE (such as calcium, histidine, human albumin, polyethylene glycol, polysorbate-80 and sodium).

Tell your healthcare provider if you are pregnant or breast-feeding because RECOMBINATE may not be right for you.

How should I use RECOMBINATE [Antihemophilic Factor

(Recombinant)]?

RECOMBINATE is given directly into the blood stream.

You may infuse RECOMBINATE at a hemophilia treatment center, at your

healthcare provider’s office or in your home. You should be trained on how to do

infusions by your hemophilia treatment center or healthcare provider. Many

people with hemophilia A learn to infuse their RECOMBINATE by themselves or

with the help of a family member.

You must carefully follow your doctor’s or other healthcare provider’s

instructions regarding the dose and schedule for infusing RECOMBINATE so

that your treatment will work best for you.

Your healthcare provider will tell you how much RECOMBINATE to use based

on your weight, the severity of your hemophilia A, and where you are bleeding.

You may have to have blood tests done after getting RECOMBINATE to be sure

that your blood level of Factor VIII is high enough to clot your blood.

Call your healthcare provider right away if your bleeding does not stop after

taking RECOMBINATE.

What should I tell my healthcare provider before I use RECOMBINATE

[Antihemophilic Factor (Recombinant)]?

You should tell your healthcare provider if you

have or have had any medical problems.

take any medicines, including non-prescription medicines, dietary

supplements and herbal remedies.

have any allergies, including allergies to mouse, hamster or bovine

proteins.

are nursing.

are pregnant or planning to become pregnant.

have been told that you have inhibitors to Factor VIII (because Factor VIII

may not work for you).

What are the possible side effects of RECOMBINATE [Antihemophilic

Factor (Recombinant)]?

You could have an allergic reaction to RECOMBINATE.

Call your healthcare provider right away and stop treatment if you get a:

Rash or hives

itching

tightness of the throat

chest pain or tightness

difficulty breathing

light-headed, dizziness

fainting.

The most common side effects are chills, flushing, rash and nose bleeds. These

are not all possible side effects with RECOMBINATE. You can ask your

healthcare provider for information that is written for healthcare professionals.

Tell your doctor about any side effect that bothers you or that does not go away.

What are the RECOMBINATE [Antihemophilic Factor (Recombinant)]

dosage strengths?

RECOMBINATE comes in five different dosage strengths. The actual strength

will be imprinted on the label and on the box. The five different strengths are

coded, as follows:

Light-blue Nominal dosage strength of approximately 250 IU per vial (220 –

400 IU/vial).

Pink Nominal dosage strength of approximately 500 IU per vial (401 –

800 IU/vial).

Green Nominal dosage strength of approximately 1000 IU per vial (801 –

1240 IU/vial).

Purple Nominal dosage strength of approximately 1500 IU per vial

(1241-1800 IU/vial)

Orange Nominal dosage strength of approximately 2000 IU per vial

(1801-2400 IU/vial)

Always check the potency printed on the label to make sure you are using the

strength prescribed by your doctor. Always check the expiration date printed on

the box. You should not use the product after the expiration date printed on the

box.

How do I store RECOMBINATE [Antihemophilic Factor (Recombinant)]?

RECOMBINATE vials containing powdered product (without sterile diluent

added) should be stored in a refrigerator (2° to 8°C [36° to 46°F]) or at room

temperature (up to 30°C [86°F]).

If you choose to store RECOMBINATE at room temperature:

it should remain at room temperature until infused.

do not put room temperature product back in the refrigerator..

Store vials in their original box and protect them from extreme exposure to light.

Do not freeze.

Reconstituted product (after mixing dry product with wet diluent) must be used

within 3 hours and cannot be stored or refrigerated. Any RECOMBINATE left in

the vial at the end of your infusion should be discarded.

What else should I know about RECOMBINATE [Antihemophilic Factor

(Recombinant)] and hemophilia A?

Your body may form inhibitors to Factor VIII. An inhibitor is part of the body’s

normal defense system. If you form inhibitors, it may stop RECOMBINATE from

working properly. Call your healthcare provider right away if your bleeding does

not stop after taking RECOMBINATE. Consult with your healthcare provider to

make sure you are carefully monitored with blood tests for the development of

inhibitors to Factor VIII.

Resources at Baxter available to the patients:

Contact Baxter to receive more product information:

Baxter Customer Service 1-800-423-2090

Baxter, RECOMBINATE, and HEMOFIL are trademarks of Baxter International

Inc.

Manufactured by:

Baxter Healthcare Corporation

Westlake Village, CA 91362 USA

U.S. License No. 140

Printed in USA

Issued: March 2010

RECOMBINATE

Antihemophilic Factor (Recombinant)

(For intravenous use only)

1. In a quiet place, prepare a clean surface. Let the vial with the FVIII concentrate and the

Sterile Water for Injection (diluent) warm up to room temperature.

2. After washing your hands and putting on sterile gloves, remove caps from the

concentrate and diluent vial to expose the centers of the rubber stoppers.

3. Disinfect the stoppers with an alcohol swab or other suitable solution suggested by your

doctor or hemophilia center.

4. Remove the protective covering from one end of the double-ended transfer needle.

5. Insert the exposed short part of the needle through the diluent stopper.

6. Remove the protective covering from the other end of the double-ended transfer needle.

7. Insert the free end of the needle through the concentrate vial stopper at its center. The

vacuum in the vial will draw in the diluent. Invert the diluent vial over the upright

concentrate vial.

8. Disconnect the two vials by removing the needle from the diluent vials stopper, then

remove the needle from the concentrate vials. Do not recap the needle! Place the needle

in a hard-walled Sharps container for proper disposal.

9. Gently roll the vial between palms until all material is dissolved. Do not shake. Check to

make sure the product is completely dissolved.

10. Attach filter needle to a disposable syringe and draw back the plunger to allow air into

the syringe. Insert the needle into the reconstituted FVIII concentrate. Inject air into the

vial.

11. Withdraw the solution into the syringe.

12. Prepare the injection site by wiping with an alcohol swab or other suitable solution

suggested by your doctor or hemophilia center.

13. Remove and discard the filter needle from the syringe; attach a suitable needle. Use a

winged infusion set if available. Do not infuse the product any faster than 5 mL per

minute for RECOMBINATE dissolved with 5 mL of sWFI. After infusion, apply

pressure with sterile gauze to the infusion site for 3 minutes. Do not recap the needle

after infusion. Place it with the used syringe in a hard-walled Sharps container for proper

disposal.

Redness of the skin or irritation may be seen when infusing RECOMBINATE dissolved

with 5 mL diluent.

14. After infusion, remove peel-off label from the concentrate vial and place it in your factor

log. Clean up any spilled blood with freshly prepared 10% bleach solution or soap and

water.

IMPORTANT: Contact your doctor or local Hemophilia Treatment Center if you

experience any problems.